1. Module 3 Testosterone therapy
Approval Number: G.MKT.GM.MH

2. Testosterone: use and misuse in men
The main indication for testosterone use in men is male hypogonadism
Other known uses and misuses include:
Use
Condition
Licensed clinical applications
Male hypogonadism
Primary, secondary or adult-onset
Delayed puberty
Aplastic and renal anemia
Off-label and experimental applications
Excessive growth
Male contraception
Obsolete application
Idiopathic infertility
Misuse/abuse
Sports performance enhancement, bodybuilding
Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010.

3. Aim of testosterone therapy in men
To restore testosterone levels to the physiological range in men with consistently low levels of serum testosterone and associated symptoms of androgen deficiency1
To improve QoL, sense of well-being, sexual function, muscle strength and bone mineral density1
Qualities of the ‘ideal’ testosterone therapy:2
Achieve and maintain a physiological level of testosterone
Ensure a favorable safety profile
Convenient dosing schedule and administration
Reasonable cost to the patient
QoL, quality of life
1. Dohle GR et al. EAU guidelines on male hypogonadism Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095–106.

4. Testosterone therapy in men: main indications
Delayed puberty (constitutional or congenital forms: hypogonadotrophic hypogonadism, Kallmann syndrome)
Klinefelter syndrome with hypogonadism
Sexual dysfunction and low testosterone, not responding to PDE-5 inhibitors
Low bone mass in hypogonadism
Adult men with low testosterone PLUS consistent and preferably multiple signs and symptoms of hypogonadism following unsuccessful treatment of obesity and comorbidities
Hypopituitarism
PDE-5, phosphodiesterase type 5
Dohle GR et al. EAU guidelines on male hypogonadism

5. Testosterone therapy in men: main contraindications
Locally advanced or metastatic prostate cancer
Male breast cancer
Men with an active desire to have children
Hematocrit >0/54%
Severe chronic cardiac failure (New York Heart Association Class IV)
Dohle GR et al. EAU guidelines on male hypogonadism

6. Marketed products for testosterone therapy
A variety of preparations containing testosterone or testosterone esters are available for the treatment of male hypogonadism
Intramuscular depot injections
Transdermal patches
and gels
Oral and buccal formulations
Subdermal depot implants
Short-acting
Long-acting (Nebido®)
Dohle GR et al. EAU guidelines on male hypogonadism Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010.

7. Available testosterone therapies: long-acting intramuscular preparation
Administration route
Formulation
Advantages
Disadvantages
Long-acting intramuscular injection
1000 mg1
Every 10–14 weeks1–3
Testosterone undecanoate
(Nebido®)
Maintains steady state physiological serum testosterone levels without fluctuation3
Long-acting preparation: requires less frequent administration,1 and allows for greater convenience2
Better adherence versus other testosterone therapies4
Well-tolerated in long-term use1,2
Long-acting preparation: does not allow rapid withdrawal in case of poor tolerability/ adverse events3
Relatively high cost2,5
1. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095– Dohle GR et al. EAU guidelines on male hypogonadism Isidori AM et al. Eur Urol. 2014;65(1):99– Seftel A. Int J Impot Res. 2007;19(1):2–24.

8. Available testosterone therapies: short-acting intramuscular preparations
Administration route
Formulation
Advantages
Disadvantages
Short-acting intramuscular injection
200 mg1
Every 2–3 weeks2
200–250 mg1,3
Testosterone cypionate
Testosterone
enanthate
Short-acting preparation: allows rapid withdrawal in case of poor tolerability/ adverse events2
Relatively low cost1
Serum testosterone concentrations fluctuate markedly outside of physiological range, with corresponding negative effects on mood, well-being and sexual function2–4
Associated with increased rates of erythrocytosis (up to 40% of patients)2
Risk of injection-site reactions (33% of users; none leading to discontinuation)4
Short-acting preparation: requires more frequent administration2
Poor adherence (3- and 12-month discontinuation rates of 69% and 95%, respectively, in a review of a US claims database)5
1. Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095– Dohle GR et al. EAU guidelines on male hypogonadism Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, Seftel A. Int J Impot Res. 2007;19(1):2– Donatucci C et al. J Sex Med. 2014;11(8):2092–9.

9. Available testosterone therapies: topical transdermal preparations
Administration route
Formulation
Advantages
Disadvantages
Topical transdermal gel
5 g2
Once-daily1–3
Testosterone
Maintains serum testosterone concentrations within the physiological range2,3
Provides longer-lasting elevations of serum testosterone than patches4
Avoids hepatic first-pass metabolism4
Requires daily administration1,2
Risk of interpersonal transfer1–3
Risk of application-site reactions (up to 5% of users)3,4
Risk of skin irritation (~5–6% of users)1–4
Relatively high cost2
Poor adherence (6- and 12-month discontinuation rates of 65.3% and 84.6%, respectively, in a review of a US claims database)5
Topical transdermal skin patch
5 mg1,2
Once-daily1,2
Mimics physiological circadian rhythm of endogenous testosterone production1,2
Risk of application-site reactions (e.g. pruritis in 37% of users)4
Risk of skin irritation (19–66% of users)1,2,4
May be cosmetically unappealing4
Poor long-term adherence (12-month discontinuation rate of 81% in a review of topical TTh use from a US claims database)6
TTh, testosterone therapy
1. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095– Dohle GR et al. EAU guidelines on male hypogonadism Seftel A. Int J Impot Res. 2007;19(1):2– Schoenfeld MJ et al. J Sex Med. 2013;10(5):1401– Grabner M et al. J Sex Med. 2018;15(2):148–58.

10. Available testosterone therapies: subdermal depot implants
Administration route
Formulation
Advantages
Disadvantages
Subdermal depot implant
200–800mg1,2
Every 5–7 months2,3
Testosterone
Long duration of action/long-lasting effect (4–6 months)1,3
Maintains constant serum testosterone concentrations1,3,4
Requires minor surgery with possibility of minor bleeding1,2,4
Risk of infection1–3
Risk of pellet extrusion (up to 10% of users)1–4
Relatively high cost2
1. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095– Dohle GR et al. EAU guidelines on male hypogonadism Seftel A. Int J Impot Res. 2007;19(1):2–24.

11. Available testosterone therapies: oral and buccal preparations
Administration route
Formulation
Advantages
Disadvantages
Oral capsule
40–80 mg1,2
2–6 every 6 h3
Testosterone undecanoate
Absorbed through the lymphatic system, with consequent reduction of liver involvement;3 most of the oral dose is hydrolyzed in the gut wall and metabolites are absorbed into the portal circulation4
Suitable for men who cannot be given intramuscular injections1,4
Serum testosterone concentrations fluctuate widely and do not mimic physiological conditions1,3
Poor predictability of individual absorption patterns1
Need for several doses per day with intake of fatty food2,3
Risk of nausea and/or other gastrointestinal complaints (~40% of users)2,4
Relatively high cost2,4
Buccal mucoadhesive tablet
30 mg2
Twice-daily1
Testosterone
Rapid absorption and achievement of physiological serum testosterone concentrations1–3
Avoids hepatic first-pass metabolism4
Irritation and pain at the application site may occur2,3
Users may experience bitter taste or dysgeusia during use4
Adherence of buccal system to the gum may be problematic5
Relatively high cost2
1. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, Edelstein D & Basaria S. Expert Opin Pharmacother. 2010;11(12):2095– Dohle GR et al. EAU guidelines on male hypogonadism Seftel A. Int J Impot Res. 2007;19(1):2– Ross RJ et al. Eur J Endocrinol. 2004;150(1):57–63.

12. Pharmacokinetic profiles of the various preparations
Module 3: Testosterone therapy
Pharmacokinetic profiles of the various preparations

13. Mean (± SD) total serum testosterone (nmol/L)
Mean serum testosterone concentrations in hypogonadal men using either a transdermal testosterone patch or transdermal testosterone gel
Mean (± SD) total serum testosterone (nmol/L)
Time (days)
Normal testosterone range (12–35 nmol/L)
Testosterone gel 5 mg/day (n=73)
Testosterone gel 10 mg/day (n=78)
Testosterone patch 5 mg/day (n=76)
An open-label, randomized, multicenter, parallel-group study investigated the pharmacokinetics after 1, 30, 90 and 180 days of daily application of 2 doses of testosterone gel (50 and 100 mg testosterone in 5 and 10 g gel, delivering 5 and 10 mg testosterone/day, respectively) or a permeation-enhanced testosterone patch (2 patches delivering 5 mg testosterone/day) in 227 hypogonadal men [serum total testosterone concentrations ≤10.4 nmol/L (300 ng/dL)].
N=227 hypogonadal men [total testosterone: ≤10.4 nmol/L (300 ng/dL)] aged 19–68 years who used daily testosterone gel (either 5 or 10 mg testosterone/day) or testosterone patches (5 mg testosterone/day) for up to 180 days SD, standard deviation
Swerdloff RS et al. J Clin Endocrinol Metab. 2000;85(12):4500–10.

14. Mean serum testosterone concentrations in hypogonadal men using buccal testosterone
Mean (± SD) total serum testosterone (nmol/L)
Time (h)
Normal testosterone range (12–35 nmol/L)
Buccal testosterone 30 mg application
An open-label, single-arm, multicenter, prospective Phase 3 trial investigated the pharmacokinetics of a mucoadhesive buccal testosterone 30 mg system in 98 hypogonadal men (mean serum total testosterone concentration: 5.2 nmol/L).
The system was applied twice-daily (12-h dosing intervals) for 3 months.
N=98 hypogonadal men [mean total testosterone: 5.2 nmol/L (150 ng/dL)] (mean age: 53.9 years) who received twice-daily buccal testosterone 30 mg for 3 months SD, standard deviation
Wang C et al. J Clin Endocrinol Metab. 2004;89(8):3821–9.

15. Mean (± SEM) total serum testosterone (nmol/L)
Mean serum testosterone concentrations in hypogonadal men using subdermal depot implants
Mean (± SEM) total serum testosterone (nmol/L)
Time (days) 30 20 10 7 5 3 2 1
Normal testosterone range (12–35 nmol/L)
An open-label, single-arm, non-randomized, prospective trial investigated the pharmacokinetics of 6 x 200 mg testosterone pellets implanted in the subdermal fat tissue of the lower abdominal wall of 14 hypogonadal men (mean serum total testosterone concentration: 1.17 nmol/L).
Blood samples for determination of testosterone concentrations were obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h, and on day 21 after implantation, and then every 3 weeks until day 188, then on days 246 and 300 of follow-up.
N=14 hypogonadal men [mean total testosterone: 1.17 nmol/L (34 ng/dL)] (mean age: years) who were implanted with six subdermal depot testosterone 200 mg implants (1200 mg total dose) and followed for 300 days SEM, standard error of the mean
Jockenhövel F et al. Clin Endocrinol (Oxf). 1996;45(1):61–71.

16. Summary
Appropriate use of testosterone therapy is effective for the management of hypogonadal symptoms
Available testosterone preparations include:
Intramuscular depot injections
Transdermal patches and gels
Oral and buccal formulations
Subdermal depot implants
These differ in their pharmacokinetic profiles, and have specific advantages and disadvantages, which can influence the hypogonadal patient’s decision to use a particular formulation